The minimum clinically important difference of the incremental shuttle walk test in bronchiectasis: a prospective cohort study.

The incremental shuttle walk test (ISW) is an externally-paced field walking test that measures maximal exercise capacity1 and is widely used in patients with chronic obstructive pulmonary disease (COPD) undergoing pulmonary rehabilitation (PR). Its psychometric properties, including reliability, construct validity2 and responsiveness to intervention,2-5 have been demonstrated in patients with bronchiectasis, but little data exist on the minimum clinically important difference (MCID). Although two studies have investigated the MCID of ISW in patients with bronchiectasis, the generalisability of these data is limited because of the study sample characteristics,6 or did not involve an exercise-based intervention.2 The MCID enables clinicians and researchers to understand the clinical significance of change data and forms an important part of the evidence required by regulatory agencies for approval for use in clinical trials. Accordingly, the aim of this study was to provide MCID estimates of the ISW in response to intervention, namely PR, in patients with bronchiectasis

Comparing performance of primary care clinicians in the interpretation of SPIROmetry with or without Artificial Intelligence Decision support software (SPIRO-AID): a protocol for a randomised controlled trial.

INTRODUCTION: Spirometry is a point-of-care lung function test that helps support the diagnosis and monitoring of chronic lung disease. The quality and interpretation accuracy of spirometry is variable in primary care. This study aims to evaluate whether artificial intelligence (AI) decision support software improves the performance of primary care clinicians in the interpretation of spirometry, against reference standard (expert interpretation). METHODS AND ANALYSIS: A parallel, two-group, statistician-blinded, randomised controlled trial of primary care clinicians in the UK, who refer for, or interpret, spirometry. People with specialist training in respiratory medicine to consultant level were excluded. A minimum target of 228 primary care clinician participants will be randomised with a 1:1 allocation to assess fifty de-identified, real-world patient spirometry sessions through an online platform either with (intervention group) or without (control group) AI decision support software report. Outcomes will cover primary care clinicians' spirometry interpretation performance including measures of technical quality assessment, spirometry pattern recognition and diagnostic prediction, compared with reference standard. Clinicians' self-rated confidence in spirometry interpretation will also be evaluated. The primary outcome is the proportion of the 50 spirometry sessions where the participant's preferred diagnosis matches the reference diagnosis. Unpaired t-tests and analysis of covariance will be used to estimate the difference in primary outcome between intervention and control groups. ETHICS AND DISSEMINATION: This study has been reviewed and given favourable opinion by Health Research Authority Wales (reference: 22/HRA/5023). Results will be submitted for publication in peer-reviewed journals, presented at relevant national and international conferences, disseminated through social media, patient and public routes and directly shared with stakeholders. TRIAL REGISTRATION NUMBER: NCT05933694

Stability and Release Kinetics of an Advanced Gliclazide-Cholic Acid Formulation: The Use of Artificial-Cell Microencapsulation in Slow Release Targeted Oral Delivery of Antidiabetics

Introduction: In previous studies carried out in our laboratory, a bile acid (BA) formulation exerted a hypoglycaemic effect in a rat model of type-1 diabetes (T1D). When the antidiabetic drug gliclazide (G) was added to the bile acid, it augmented the hypoglycaemic effect. In a recent study, we designed a new formulation of gliclazide-cholic acid (G-CA), with good structural properties, excipient compatibility and exhibits pseudoplastic-thixotropic characteristics. The aim of this study is to test the slow release and pH-controlled properties of this new formulation. The aim is also to examine the effect of CA on G release kinetics at various pH values and different temperatures. Method: Microencapsulation was carried out using our Buchi-based microencapsulating system developed in our laboratory. Using sodium alginate (SA) polymer, both formulations were prepared: G-SA (control) and G-CA-SA (test) at a constant ratio (1:3:30), respectively. Microcapsules were examined for efficiency, size, release kinetics, stability and swelling studies at pH 1.5, pH 3, pH 7.4 and pH 7.8 and temperatures of 20 and 30 °C. Results: The new formulation is further optimised by the addition of CA. CA reduced microcapsule swelling of the microcapsules at pH 7.8 and pH 3 at 30 °C and pH 3 at 20 °C, and, even though microcapsule size remains similar after CA addition, percent G release was enhanced at high pH values (pH 7.4 and pH 7.8, p < 0.01). Conclusion: The new formulation exhibits colon-targeted delivery and the addition of CA prolonged G release suggesting its suitability for the sustained and targeted delivery of G and CA to the lower intestine

In Vitro and In Vivo Antagonism of a G Protein-Coupled Receptor (S1P3) with a Novel Blocking Monoclonal Antibody

Background: S1P 3 is a lipid-activated G protein-couple receptor (GPCR) that has been implicated in the pathological processes of a number of diseases, including sepsis and cancer. Currently, there are no available high-affinity, subtypeselective drug compounds that can block activation of S1P3. We have developed a monoclonal antibody (7H9) that specifically recognizes S1P3 and acts as a functional antagonist. Methodology/Principal Findings: Specific binding of 7H9 was demonstrated by immunocytochemistry using cells that over-express individual members of the S1P receptor family. We show, in vitro, that 7H9 can inhibit the activation of S1P3mediated cellular processes, including arrestin translocation, receptor internalization, adenylate cyclase inhibiton, and calcium mobilization. We also demonstrate that 7H9 blocks activation of S1P3 in vivo, 1) by preventing lethality due to systemic inflammation, and 2) by altering the progression of breast tumor xenografts. Conclusions/Significance: We have developed the first-reported monoclonal antibody that selectively recognizes a lipidactivated GPCR and blocks functional activity. In addition to serving as a lead drug compound for the treatment of sepsi

Co-ordinated Role of TLR3, RIG-I and MDA5 in the Innate Response to Rhinovirus in Bronchial Epithelium

The relative roles of the endosomal TLR3/7/8 versus the intracellular RNA helicases RIG-I and MDA5 in viral infection is much debated. We investigated the roles of each pattern recognition receptor in rhinovirus infection using primary bronchial epithelial cells. TLR3 was constitutively expressed; however, RIG-I and MDA5 were inducible by 8–12 h following rhinovirus infection. Bronchial epithelial tissue from normal volunteers challenged with rhinovirus in vivo exhibited low levels of RIG-I and MDA5 that were increased at day 4 post infection. Inhibition of TLR3, RIG-I and MDA5 by siRNA reduced innate cytokine mRNA, and increased rhinovirus replication. Inhibition of TLR3 and TRIF using siRNA reduced rhinovirus induced RNA helicases. Furthermore, IFNAR1 deficient mice exhibited RIG-I and MDA5 induction early during RV1B infection in an interferon independent manner. Hence anti-viral defense within bronchial epithelium requires co-ordinated recognition of rhinovirus infection, initially via TLR3/TRIF and later via inducible RNA helicases

Outcomes analysis of new entrant screening for active tuberculosis in Heathrow and Gatwick airports, United Kingdom 2009/2010

BACKGROUND: In 2012, the United Kingdom (UK) Government announced that the new entrant screening for active tuberculosis (TB) in Heathrow and Gatwick airports would end. Our study objective was to estimate screening yield and diagnostic accuracy, and identify those at risk of active TB after entry. METHODS: We designed a retrospective cohort study and linked new entrants screened from June 2009 to September 2010 through probabilistic matching with UK Enhanced TB Surveillance (ETS) data (June 2009 to December 2010). Yield was the proportion of cases reported to ETS within three months of airport screening in the screened population. To estimate screening diagnostic accuracy we assessed sensitivity, specificity, positive and negative predictive values. Through Poisson regression we identified groups at increased risk of TB diagnosis after entry. RESULTS: We identified 200,199 screened entrants, of these 59 had suspected TB at screening and were reported within 3 months to ETS (yield = 0.03 %). Sensitivity was 26 %; specificity was 99.7 %; positive predictive value was 13.2 %; negative predictive value was 99.9 %. Overall, 350 entrants were reported in ETS. Persons from countries with annual TB incidence higher than 150 cases per 100,000 population and refugees and asylum seekers were at increased risk of TB diagnosis after entry (population attributable risk 77 and 3 % respectively). CONCLUSION: Airport screening has very low screening yields, sensitivity and positive predictive value. New entrants coming from countries with annual TB incidence higher than 150 per 100,000 population, refugees and asylum seekers should be prioritised at pre- or post-entry screening